This invention relates to a method of treating vaginal dryness by administering to a patient a nicotinic acetylcholine receptor agonist such as nicotine, epibatidine alkaloids and their analogs thereof.
Vaginal dryness is a very common problem which brings physical and emotional distress to many women (Key, E., Nurs. Stand. 5:24-27 (1991)). It most commonly manifests itself during sexual intercourse, which causes dyspareunia and can eventually lead to apareunia. Although it is traditionally considered to be a condition which affects postmenopausal women, it can occur during the premenopausal and perimenopausal years. The use of oral contraceptives may also cause a reduction in vaginal moisture in some women (Reginald, W., et al., Br. J. Obstet. Gynaecol. 96:1148-1152 (1989)). Postpartum vaginal dryness, independent of or as a result of lactation, can be a significant complaint (Wisniewski, P., et al., Am. J. Obstet. Gynecol. 165:1249-1254 (1991)). Women undergoing chemotherapy or radiotherapy for malignant diseases such as leukemia often experience vaginal dryness as a result of treatment (Cust, M., et al., Br. Med. J. 299:1494-1497 (1989)). Many disease states, such as systemic sclerosis and other systemic autoimmune disorders (Bhadauria, S., et al., Am. J. Obstet. Gynecol. 172:580-587 (1995)), Ehlers-Danlos syndrome (Sorokin, Y., et al., J. Reprod. Med. 39:281-284 (1994)), diabetes mellitus (Sreebny, L., et al., Diabetes Care 15:900-904 (1992)), and Sjxc3x6gren""s syndrome (Marchesoni, D., et al., Eur. J. Obstet. Gynecol. Reprod. Biol. 63:49-53 (1995)) have decreased vaginal hydration and lubrication problems as significant disease-associated symptoms.
Vulvar pain is defined as the excessive sensitivity of the nerves supplying the mucus membrane of the vulva. This persistent burning and sensitivity in vulvar skin is not caused by identifiable infection. It cannot be cured by surgery. The diseases covered under xe2x80x9cvulvar painxe2x80x9d are also referred to as vulvodynia/vulvar vestibulitis, vulvitis, burning vulvar syndrome and is often associated with fibromyalgia, irritable bowel syndrome, Sjxc3x6gren""s syndrome, chronic inflammation, and Paget""s disease as well as in the absence of any identifiable disease or infection.
Current therapies for increasing vaginal moisture are: lubricating agents such as lubricating creams or jellies, topical estrogen creams, and HRT (hormone replacement therapy). Lubricating jellies provide short-lived and temporary relief, as these are aqueous preparations containing no pharmacologically active agent. Topical estrogen creams, if used on a regular basis, may be absorbed into the systemic circulation. This can cause endometrial stimulation and can lead to endometrial hyperplasia and carcinoma (Whitehead, M., et al., N. Eng. J. Med. 305:1599-1605 (1981)). HRT is effective at relieving symptoms of vaginal atrophy and hence vaginal dryness but has several contraindications and unwanted risks and side effects.
A history of gall bladder disease (N. Eng. J. Med., 290:15-19 (1974)) or a personal or family history of reproductive or breast cancer (Harlap, S., Am. J. Obstet. Gynecol. 166:1986-1992 (1992)) are contraindications for estrogen therapy. Other contraindications are: history of stroke, cardiovascular disease, deep-vein thrombosis, superficial thrombophlebitis, liver disease, heavy smoking, high blood pressure, diabetes, uterine bleeding or large fibroids, hyperlipidemia, and gross obesity (Lichtman, R., J. Nurse Midwifery 36:30-48 (1991)). One major disadvantage of HRT is the resumption of monthly withdrawal bleeds, which many postmenopausal women will not accept. Some women, even while on HRT, still experience a degree of vaginal dryness (Key, E., Nurs. Stand. 5:24-27 (1991)).
Mucus is a viscous, lubricating material that recruits and maintains moisture to the surfaces it coats. Mucus is actively secreted with salt and water onto surfaces that require these hydrating and lubricating properties for normal functioning (Forstner et al., Adv. Exp. Med. Biol. 144:199-224 (1982)). The mucus covering on the surfaces of the female reproductive tract is important in its defense and reproductive function. The mucus gel, secreted primarily by the endocervical epithelium, provides a barrier to sperm and pathogen penetrance into the endometrium and a protective covering for the vaginal epithelium. The hydration of vaginal and cervical mucus prevents atrophy, provides lubrication during intercourse, aids surface defense against pathogens, and modulates sperm entry into the uterus, etc. (see Gipson I. K., et al., Biology of Reproduction, 60, 58-64 (1999))
Nicotinic acetylcholine receptors (nAChRs), present in a variety of tissues, are heterologous receptors made up of several subunits. Various nAChR subtypes exist and they show a complex regulation of calcium concentration and mediation of neurotransmitter (e.g. dopamine) release.
Nicotinic agonists have many pharmacological actions when applied locally or systemically, and synthetic compounds are being targeted towards a number of therapeutic indications including: Alzheimer""s disease, Parkinson""s disease, smoking cessation, epilepsy, neuroprotection, attention deficit disorder and pain (Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities, Eds. Arneric and Brioni, Wiley-Liss, Inc. (1999)). Nicotinic agonists, such as nicotine, stimulate the secretion of mucus when applied to the mucosal surfaces of the lung and stomach, and is believed to have protective effects on ulcerative colitis presumably by increasing colonic mucin secretion (Morris, et al., J. Clin Gastroenterol, 27:S53-63 (1998), Finnie, et al., Clin. Sci., 91:359-364 (1996), Zijlstra, et al., Gut, 35:247-251 (1994); Kaunitz, et al., J. Pharmacol. Exp. Ther., 265:948-954 (1993)). Transdermnal nicotine has been used clinically as therapy for ulcerative colitis (Pullen, Ann. R. Coll. Surg. Engl. 78:85-91 (1996)).
The nicotine-associated effects of cigarette smoking have been studied extensively and it is well established that tobacco smoking leads to chronic bronchitis and mucus hypersecretion (Coles, et al., Am. J. Pathology, 94:459-471 (1979); Wanner, et al., Am. J. Respir. Crit. Care Med., 154:1868-1902, (1996). xe2x80x9cTopicalxe2x80x9d tobacco smoke causes mucin secretion from airway goblet cells and systemic nicotine causes increased tracheal mucus secretion (Kuo, et al., Am. J. Physiol. 263:L161-167 (1992); Lang, et al.; Klin. Wochenschr. 66:170-179 (1988); Hummer, et al., Klin. Wochenschr. 66:161-169 (1988), Richardson, et al., Eur. J. Respir. Dis. Suppl. 153:43-51 (1987)). These pro-secretory effects of nicotine have been largely thought of as deleterious, with the exception of the association of less frequent ulcerative colitis among cigarette smokers.
Recent advances in the field of nicotine receptors has revealed that it is possible to create ligands for specific nicotinic receptor subtypes, thereby reducing or eliminating altogether the unwanted side effects of nicotine, such as neuromotor and cardiovascular effects (Brioni et al., Behav. Neural. Biol. 59:57-62 (1993); Brioni, et al., Adv. Pharmacol. 37:153-214 (1997)) The field of therapeutic nicotinic agonists largely focuses on the central nervous system effects of nicotinic agonists and their ability to stimulate cognition (U.S. Pat. Nos. 5,922,723 and 5,861,423). The mild antiinflammatory effects of nicotine are established; smokers have been shown to have a lower incidence of inflammatory diseases such as ulcerative colitis, sarcoidosis, pigeon breeder""s disease, farmer""s lung, allergies, endometriosis, uterine fibroids and acne (Arneric and Brioni Ch. 11, p. 205). Nicotine has also been investigated for its effects on CNS inflammation (Brioni, et al., (1997), supra) based diseases.
Because of the ability of nicotinic agonists to stimulate secretion in the lung and gastrointestinal tract, Applicants were motivated to investigate whether nicotinic agonists could effect hydration and lubrication of the vaginal and cervical tissues, and thus be effective in treating vaginal dryness. Applicants have discovered that nicotinic receptor agonists, when given topically or systemically, provide a therapeutic effect of treating vaginal dryness by increasing the hydration and lubricating properties of vaginal and cervical tissues.
The invention provides a method of stimulating cervical and vaginal secretion in a subject in need. The method comprises administering to a patient a pharmaceutical composition comprising a nicotinic acetylcholine receptor agonist in an amount effective to increase cervical and vaginal hydration.
The pharmaceutical composition used in this invention comprises a nicotinic receptor agonist together with a pharmaceutically acceptable carrier thereof. Nicotinic receptor agonists include but are not limited to: nicotine and its analogs, trans-metanicotine and its analogs, epibatidine and its analogs, pyridol derivatives, piperidine alkaloids such as lobeline and its analogs, certain para-alkylthiophenol derivatives, and imidacloprid and its analogs.
The compounds of the present invention are potent agonists of nicotinic receptors; thus, they are useful in the treatment of vaginal dryness in which hydration and lubrication of vaginal and cervical tissues are impaired.